Context:
Acute diarrheal disease is the most frequent childhood illness and cause for attending public health facilities in low-income and middle-income countries. Severe childhood diarrhea is among the leading causes of hospital admissions in low-income and middle-income countries. Globally, diarrhea is the fourth leading cause of DALYs (Disability Adjusted Life Years), with half of the DALYs due to diarrhea potentially preventable in the age group of 1-11 months.[1]
Dehydration is one of the main complications of diarrhea, which was treated with intravenous fluids until 1960s. Mortality due to diarrhea reduced substantially after the introduction of Oral Rehydration Therapy in 1979.[2] WHO first introduced ORS in 1975 designed mainly to treat children from diarrhea from cholera. Subsequently, it was found that although the standard WHO-ORS corrected dehydration, it does not reduce the volume of stool and duration of diarrhea.[3] Standard WHO-ORS has a total osmolarity of 311 mmol/L with 90 mmol/L of sodium and 111 mmol/L of glucose. Studies suggest that hypotonic ORS containing 50-60 mmol/L sodium and 90-100 mmol/L glucose produce maximal water absorption.[4] Therefore, the current review aims to evaluate the efficacy of low osmolar ORS in comparison to standard WHO-ORS in reducing the stool output, vomiting episodes and duration of diarrhea through meta-analysis of randomized controlled trials.
Evidence Acquisition
Criteria for considering studies for review:
Studies:
Randomized controlled trials were included in this review (quasi-randomized trials were excluded).
Participants: Children presenting with a complaint of diarrhea were included in this review. Adults were excluded from this review as the authors opined that ORS distribution in the public health facilities is mainly concentrated on children.
Interventions: Trials comparing low osmolar ORS (osmolarity 250 mmol/L or less) with standard WHO-ORS (90 mmol/L sodium, 111 mmol/L glucose, total osmolarity 311 mmol/L).
Outcomes: Pre-defined outcomes were stool output, duration of diarrhea, episodes of vomiting and intravenous fluid therapy during the course of treatment.
Search strategy for documentation of studies: Clinical trials were searched in PubMed, Cochrane CENTRAL, DOAJ, Google Scholar and Google. The detailed search strategy used in PubMed and Cochrane CENTRAL is mentioned in Table 1. The review is updated till September 2013.
Table 1: Search strategy |
| Search strategy for Cochrane CENTRAL |
No. |
Search terms |
No. of trials |
#1 |
MeSH descriptor: [Fluid Therapy] explode all trees |
1127 |
#2 |
"oral rehydration salt":ti,ab,kw (Word variations have been searched) |
56 |
#3 |
"oral rehydration solution":ti,ab,kw (Word variations have been searched) |
295 |
#4 |
low osmolar oral rehydration therapy:ti,ab,kw (Word variations have been searched) |
21 |
#5 |
low osmolar oral rehydration salt:ti,ab,kw (Word variations have been searched) |
9 |
#6 |
low osmolar oral rehydration solution:ti,ab,kw (Word variations have been searched) |
24 |
#7 |
#1 or #2 or #3 or #4 or #5 or #6 |
1272 |
#8 |
MeSH descriptor: [Diarrhea] explode all trees |
2368 |
#9 |
MeSH descriptor: [Diarrhea, Infantile] explode all trees |
438 |
#10 |
"diarrhea":ti,ab,kw (Word variations have been searched) |
8120 |
#11 |
"infantile diarrhea":ti,ab,kw (Word variations have been searched) |
101 |
#12 |
child diarrhea:ti,ab,kw (Word variations have been searched) |
1788 |
#13 |
infant diarrhea:ti,ab,kw (Word variations have been searched) |
1483 |
#14 |
childhood diarrhea:ti,ab,kw (Word variations have been searched) |
184 |
#15 |
#8 or #9 or #10 or #11 or #12 or #13 or #14 |
8120 |
#16 |
MeSH descriptor: [Randomized Controlled Trial] explode all trees |
41 |
#17 |
MeSH descriptor: [Controlled Clinical Trial] explode all trees |
2 |
#18 |
MeSH descriptor: [Clinical Trial] explode all trees |
52 |
#19 |
"randomized controlled trial":pt (Word variations have been searched) |
325572 |
#20 |
"controlled clinical trial":pt (Word variations have been searched) |
82752 |
#21 |
"clinical trial":pt (Word variations have been searched) |
297309 |
#22 |
randomized:ti,ab,kw (Word variations have been searched) |
281910 |
#23 |
"placebo":ti,ab,kw (Word variations have been searched) |
135223 |
#24 |
"randomly":ti,ab,kw (Word variations have been searched) |
88667 |
#25 |
"trial":ti (Word variations have been searched) |
120529 |
#26 |
#16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24 or #25 |
541207 |
#27 |
MeSH descriptor: [Osmolar Concentration] explode all trees |
1195 |
#28 |
"osmolar":ti,ab,kw (Word variations have been searched) |
1352 |
#29 |
osmolarity:ti,ab,kw (Word variations have been searched) |
237 |
#30 |
#27 or #28 or #29 |
1582 |
#31 |
#7 and #15 and #26 and #30 |
46 |
Search strategy for PubMed |
No. |
Search terms |
No. of trials |
#47 |
Search (#42 AND #46) |
42 |
#46 |
Search (#43 OR #44 OR #45) |
63208 |
#42 |
Search (#41 AND #37 AND #38) |
426 |
#45 |
Search osmolar*[Title/Abstract] |
8411 |
#44 |
Search osmolarity[MeSH Terms] |
58455 |
#43 |
Search osmolar concentration[MeSH Terms] |
58455 |
#41 |
Search (#40 NOT #28) |
832602 |
#38 |
Search (#15 OR #16 OR #11 OR #13 OR #14) |
14286 |
#37 |
Search (#2 OR #4 OR #7 OR #8 OR #36) |
75682 |
#40 |
Search (#20 OR #19 OR #21 OR #22 OR #24 OR #39) |
897156 |
#39 |
Search clinical trial as topic[MeSH Terms] |
267042 |
#36 |
Search infantile diarrhea*[Title/Abstract] |
648 |
#28 |
Search (animals [mh] NOT humans [mh]) |
3822660 |
#24 |
Search randomly[Title/Abstract] |
203208 |
#22 |
Search placebo[Title/Abstract] |
152125 |
#21 |
Search randomized[Title/Abstract] |
298682 |
#20 |
Search controlled clinical trial[Publication Type] |
86222 |
#19 |
Search randomized controlled trial[Publication Type] |
351756 |
#14 |
Search oral rehydration solution*[Title/Abstract] |
990 |
#13 |
Search oral rehydration salt*[Title/Abstract] |
283 |
#11 |
Search oral rehydration therapy[MeSH Terms] |
13813 |
#16 |
Search low osmolar oral rehydration salt*[Title/Abstract] |
7 |
#15 |
Search low osmolar oral rehydration solution*[Title/Abstract] |
19 |
#8 |
Search childhood diarrhea*[Title/Abstract] |
401 |
#7 |
Search infantile diarrhea[MeSH Terms] |
6421 |
#4 |
Search diarrhea[MeSH Terms] |
42496 |
#2 |
Search diarrhea*[Title/Abstract] |
53305 |
Data collection and analysis
Selection of studies: The search was done by the first author. First and second author examined the abstracts independently for inclusion and exclusion from the review. Any differences were resolved by discussion with the third author. Assessment of risk of bias was carried out as per the guidelines of Cochrane Handbook for Systematic Reviews of Interventions.[5]
Statistics: The data was extracted by first and second author and was maintained in Microsoft Excel software. The continuous data were log transformed into converted means as described in the Cochrane Handbook for Systematic Reviews of Interventions.[5] The dichotomous data were entered as it is. Data were then entered in Review Manager software version 5.3 and effect sizes were calculated. Dichotomous data (episodes of vomiting and need for intravenous infusion) were pooled in the form of Odds Ratio (with 95% CI) and continuous data (stool output and duration of diarrhea) were pooled in the form of standardized mean difference (with 95% CI).
Results
A total of 12 RCTs were included in the meta-analysis. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram recording the selection of trials and reasons for exclusion is demonstrated in Figure 1. [6]
 |
Figure 1: Flow diagram recording the selection of trials and reasons for exclusion |
The characteristics of included studies are elaborated in Table 2.
Table 2: Characteristics of included studies |
| Trial |
Alam 2000 [7] |
Methods |
Double blinded RCT |
Participants |
170 children between 3 months to 5 years old with acute cholera and non-cholera diarrhoea and some to severe dehydration |
Interventions |
1. Low osmolarity glucose ORS (245 mosmol/L)
2. WHO standard ORS |
Outcomes |
Rehydration frequency (stool/4h)
Rehydration ORS consumed (L)
Rehydration duration (h)
Maintenance frequency (stools/4h)
Maintenance ORS consumed (L)
Maintenance duration (h)
Overall frequency (stool/4h)
Overall ORS consumed (L)
Overall duration (h)
Weight gain (%)
Caloric intake (kcal/kg/d)
Serum sodium (mEq/L)
Urine output (boys) (ml/k/h)
Intravenous fluid (ml/kg) |
| |
|
Trial |
Dutta P 2000 [8] |
Methods |
Double blinded RCT |
Participants |
70 children aged 3-24 months old with some dehydration |
Interventions |
1. Low osmolar glucose ORS (224 mOsm)
2. WHO standard ORS |
Outcomes |
Duration of diarrhea
Stool output
Intake of ORS
Fluid intake (ORS + water + liquid food)
Weight gain
Serum electrolytes |
| |
|
Trial |
Khan 2005 [9] |
Methods |
Double blinded RCT |
Participants |
144 Infants aged < 2 months |
Interventions |
1. ORS 75 (245 mOsm)
2. ORS 90 (311 mOsm) |
Outcomes |
Stool output
Stool frequency
Requirement for ORS
Serum sodium at 24 hours
Vomiting in first 24 hours
Need for iv fluid
Resolution of diarrhea within 5 days |
| |
|
Trial |
Pignatelli 2003 [10] |
Methods |
Double blinded RCT |
Participants |
4000 infants and children aged < 5 years |
Interventions |
1. High osmolarity ORS (90 mEq/L Na+) solution (20 g glucose, 3.5 g NaCl, 2.5 g NaHCO3, and 1.5 g KCl, in 1 L water), administered by NGT over 3 hours, followed by a low-osmolarity (30 mEq/L Na ) solution given by NGT for 3 additional hours
2. Only low-osmolarity solution (20 g glucose, 1.2 g NaCl, 0.8 g NaHCO3, and 1.5 g KCl, in 1 L water), administered by NGT over 6 hours
3. Only high-osmolarity solution, containing glucose
and electrolytes according to the WHO guidelines, administered by NGT over
6 hours |
Outcomes |
Stool output in first 24 hours
Need for iv fluid
Vomiting in first 24 hours
Duration of diarrhea after rehydration was started |
| |
|
Trial |
Santosham 1996 [11] |
Methods |
RCT (double blind) |
Participants |
190 boys 1 to 24 months with diarrhoea and dehydration (WHO criteria) |
Interventions |
1. Low osmolarity glucose ORS (245 mosmol/L)
2. WHO standard ORS |
Outcomes |
Stool output (24 h and total)
Fluid intake
Sodium
Potassium
Weight gain
Children who vomited
Mean weight gain
Duration of diarrhoea
Treatment failures |
|
|
Trial |
Sarker 2001 [12] |
Methods |
Double blinded RCT |
Participants |
93 male children (aged 4 to 24 months) |
Interventions |
1. Rice based reduced osmolarity ORS (134 mOsm/L)
2. WHO ORS
3. Glucose based reduced osmolarity ORS (208 mOsm/L) |
Outcomes |
1. ORS requirement
2. Stool purging severity
3. Stool output
4. Unscheduled iv fluid therapy
5. Intake of plain water or formula milk |
| |
|
Trial |
Sarker SA 1995 [13] |
Methods |
RCT |
Participants |
55 children 2 to 15 months old
Randomized after 1 day of rehydration |
Interventions |
1. Low L-alanine and glucose ORS (255 mosmol/L)
2. IV
3. WHO standard ORS |
Outcomes |
Stool output (24 h, 96 h)
Unscheduled IV
Fluid intake
Food intake
Vomiting
Body weight
Stool frequency |
| |
|
Trial |
Moreno-Sánchez H 1990 [14] |
Methods |
RCT |
Participants |
186 children 1 to 36 months old with diarrhoea and dehydration |
Interventions |
1. Low osmolarity glucose ORS-90 (240 mosmol/L)
2. WHO standard ORS |
Outcomes |
Need of IV
Sodium
Potassium concentration |
|
|
Trial |
CHOICE study group 2001 [15] |
Methods |
RCT (double blind) |
Participants |
671 children
1 to 24 months old with diarrhoea and some more severe dehydration |
Interventions |
1. Low osmolarity glucose ORS (245 mosmol/L)
2. WHO standard ORS |
Outcomes |
Stool output (24 h and total)
ORS intake (24 h, total)
Vomiting in first 24 h
Unscheduled IV in the first 24 h
Frequency of hyponatraemia at 24 h
Duration of diarrhoea |
|
|
Trial |
International Study 1995 [16] |
Methods |
Multicentred RCT (double blind) |
Participants |
447 children aged 1 to 24 months admitted to hospital with diarrhoea and mild to moderate dehydration (WHO classification) |
Interventions |
1. Low osmolarity glucose ORS (224 mosmol/L)
2. WHO standard ORS |
Outcomes |
Stool output at 24 h
Fluid intake
Mean daily consumption of formula milk and semi-solid food.
Weight gain
Serum sodium on admission and at 24 h
Need for unscheduled IV |
| |
|
Trial |
El-Mougi 1994 [17] |
Methods |
RCT, no details given |
Participants |
61 children 3 to 24 months old with diarrhoea and moderate dehydration (WHO definition) |
Interventions |
1. Low osmolarity glucose ORS (210 mosmol/L)
2. WHO standard ORS
3. IV infusion |
Outcomes |
Stool volume at 24 h
Fluid intake
Weight gain at 6 h
Hyponatraemia;
Duration of diarrhoea |
| |
|
Trial |
Dutta P 2001 [18] |
Methods |
Double blind RCT |
Participants |
64 children aged 6–48 months; severely malnourished (marasmic); with dehydrating acute watery diarrhea |
Interventions |
1. Hypo-osmolar ORS (224 mmol/L)
2. WHO standard ORS |
Outcomes |
Stool output (24-72 h and at recovery)
Episodes of vomiting
Duration of diarrhea
Intake of ORS
Fluid intake
Weight gain
Recovery within 5 days |
The characteristics of excluded studies with the reasons for exclusion are illustrated in Table 3.
Table 3: Characteristics of excluded studies (reasons for exclusion of full texts from meta-analysis) |
| Trial |
Reasons for exclusion |
Yang 2007 [19] |
Not in English |
Shornikova 1997 [20] |
Comparison group was not standard WHO-ORS |
Velásquez-Jones L 1990 [21] |
Duplicate study to Moreno-Sanchez H 1990. Moreno-Sanchez H 1990 was considered for meta-analysis as it had the maximum sample size. |
Rautanen T 1993 [22] |
Comparison group was not standard WHO-ORS |
Valentiner Branth 1999 [23] |
No data relevant to the current meta-analysis |
Mallet E 1990 [24] |
Comparison group was not standard WHO-ORS |
Bhattacharya MK 1998 [25] |
Comparison group was not standard WHO-ORS, but low osmolar rice based ORS |
Rautanen T 1998 [26] |
Compared 2 low osmolar ORS (not WHO standard ORS) |
Rautanen T 1997 [27] |
Comparison group was not standard WHO-ORS |
Pulungsih SP 2006 [28] |
Included 12-60 years subjects (adults also) |
The risk of bias in each clinical trial included in the meta-analysis is elucidated in Table 4.
Table 4: Assessment of risk of bias in the trials included in the meta-analysis |
| Trials |
Random sequence generation (selection bias) |
Allocation concealment (selection bias) |
Blinding of participants and personnel (performance bias) |
Blinding of outcome assessment (detection bias) |
Incomplete outcome data (attrition bias) |
Selective reporting (reporting bias) |
Other bias |
Alam 2000 [7] |
Low |
Low |
Low |
Unclear |
Low |
Low |
Low |
CHOICE study group 2001 [15] |
Low |
Low |
Low |
Low |
Low |
Unclear |
Low |
Dutta P 2000 [8] |
High |
Low |
Low |
Unclear |
Low |
Low |
Low |
Dutta P 2001 [18] |
High |
High |
High |
Unclear |
Low |
Low |
Unclear |
El-Mougi 1994 [17] |
Low |
High |
High |
High |
Low |
Low |
Unclear |
International Study 1995 [16] |
Low |
Low |
Low |
Low |
Low |
Low |
Low |
Khan 2005 [9] |
High |
High |
Low |
Unclear |
Low |
Low |
Unclear |
Pignatelli 2003 [10] |
High |
Low |
Low |
Low |
High |
High |
High |
Santosham 1996 [11] |
Low |
Low |
Low |
High |
Low |
Unclear |
Low |
Sarker 2001 [12] |
High |
High |
Low |
High |
Low |
Low |
Unclear |
Sarker SA 1995 [13] |
Low |
Low |
Low |
Low |
Low |
High |
Unclear |
Moreno-Sánchez H 1990 [14] |
High |
High |
Low |
Unclear |
Low |
High |
Unclear |
Funnel plot to assess publication bias was not plotted as the number of clinical trials in each outcome was less than 10.
Information for the outcome of stool output was available from 9 trails (n=2261) [Figure 2].
 |
Figure 2: Forest plot for the outcome of stool output |
The outcome of stool output was measured with different units in different trials. Therefore, standardized mean difference was used to analyze this data. As the outcome of stool output was a skewed distribution, we took log-normal approximation for the same. The pooled standardized mean difference in the log scale is -0.44 (95% CI -0.72 to -0.15), suggesting that reduced osmolarity ORS resulted in significantly reduced stool output as compared with WHO standard ORS.
Information for the outcome of duration of diarrhea was available from 6 trials (n=1889) [Figure 3].
 |
Figure 3: Forest plot for the outcome of duration of diarrhea |
The pooled standardized mean difference in the log scale is -0.21 (95% CI -0.79 to 0.37), suggesting that reduced osmolarity ORS did not have significant effect on the duration of diarrhea as compared to WHO standard ORS.
Information for the outcome of need for intravenous fluid therapy was available from 8 trials (n=1775) [Figure 4].
 |
Figure 4: Forest plot for the outcome of need for intravenous fluid therapy |
The meta-analysis revealed a statistically significant reduction in for unscheduled intravenous infusion for participants receiving reduced osmolarity oral rehydration solution (ORS) when compared with WHO standard ORS was demonstrated (odds ratio 0.62, 95% CI 0.47 to 0.83).
For the outcome of children vomiting during diarrhea, the data was available from 5 clinical trials (n=1267) [Figure 5].
 |
Figure 5: Forest plot for the outcome of vomiting during diarrhea. |
The meta-analysis showed that children in the low osmolar ORS group were less likely to vomit that children in WHO standard ORS group (odds ratio 0.74, 95% CI 0.57 to 0.97).
Discussion
The present systematic review and meta-analysis observes the superiority of low osmolar ORS in comparison to WHO standard ORS in children suffering from diarrhea. The low osmolar ORS was observed to have beneficial effect in reducing stool output, unscheduled intravenous infusion and episodes of vomiting. Although, there was no difference observed in duration of diarrhea in children being treated with either ORS formulations. We intended to do subgroup analysis between patients with cholera and non-cholera diarrhea, but there was insufficient data to do so. We could not assess publication bias through funnels plots as the number of clinical trials were small to arrive at an opinion on that. Placebo-controlled double blind Randomized Controlled Trials are required to study the use of reduced osmolarity ORS in diarrhea due to cholera as diarrhea due to cholera is secretory in nature.
Oral Rehydration Solution (ORS), along with Zinc tablets, is now used as the first line of therapy to prevent dehydration due to diarrhea. ORS has got a significant amount of public health importance due to its very wide reach in terms of its use till the village health worker level. Thereby, it becomes necessary to document the effectiveness of different forms of ORS being used currently.
The current review reflects, supplements and updates the existing knowledge on low osmolar ORS. Policy makers have now shifted to the reduced osmolarity ORS for preventing dehydration due to diarrhea even in areas where cholera coexists with other diarrheas. WHO and UNICEF now recommend the use of low osmolar ORS (245 mOsm/L) for preventing dehydration due to diarrhea.
Conclusion
Low osmolar ORS when compared to standard WHO-ORS is associated with reduced stool output, reduction in need for unscheduled intravenous infusion and lesser episodes of vomiting. However, there was no significant difference in duration of diarrhea.
Key Messages
Low osmolar ORS, instead of WHO standard ORS, should be used to prevent dehydration in children suffering from diarrhea.
Acknowledgements
We thank Dr. Jaykaran Charan and Dr. Soumyadeep Bhaumik for guiding us through the process of this meta-analysis
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